Antibody induced T cell mediated neonatal autoimmunity

我们最近对自身免疫性卵巢疾病（AOD）的研究已经积累了证据，表明在生命早期抗原和环境因素的刺激使遗传易感小鼠易患早发型和晚发型自身免疫性疾病，这可以通过生命早期存在的CD 4 +CD2.5+调节性T细胞的相对缺乏来解释。我们现在提出了一个新的和引人注目的意见，进一步加强了这一范式。抗ZP 3 B细胞表位（335-342）的自身抗体（autoAb）被发现优先损伤新生小鼠的卵巢，而不损伤成年小鼠的卵巢。有趣的是，虽然卵巢疾病是由ZP 3 autoAb触发的，但疾病表达取决于新生儿中T细胞的存在，并且与新生儿自身免疫T细胞对卵巢抗原的应答相关。此外，该新生儿AOD的诱导是B细胞表位特异性的;因此针对第二ZP 3天然B细胞表位（171-180）的autoAb是非致病性的。更令人兴奋的是，只有当autoAb在出生后的前5天首次到达新生小鼠时，新生小鼠才会发生AOD。理论上，母体自身抗体可引发新生儿致病性自身T细胞反应和新生儿AOD;诱导B细胞表型特异性，并且已知仅侵袭新生儿mi_t是特异性的免疫性T细胞。我们现在提出以下实验方法来进一步研究这些新的和令人兴奋的观察结果。我们将检验以下假设：新生儿AOD是由表位特异性自身抗体与内源性Ag形成免疫复合物，诱导ZP 3特异性致病性T细胞应答和长时程自身免疫记忆。第二，我们将检验免疫复合物激活抗原呈递细胞依赖于其Fc受体的假设，并且该事件是新生儿AOD诱导所需的。第三，我们将检验新生小鼠中的CD 4 + CD 25+调节性T细胞缺陷解释新生小鼠发展自身免疫反应和疾病的倾向的假设。因此，该提案将解决负责自身免疫诱导和预防的基本机制，特别是新生儿自身免疫性疾病，包括系统性狼疮相关的先天性心脏传导阻滞。美国弗吉尼亚州西阿里奥茨维尔特大学（组织机构，y，state）

EXCEED THE SPACE PROVIDED, Our recent studies on autoJmmune ovarian disease (AOD) have accrued evidence that stimulation by antigen and environmental factor early in life predisposes genetically-susceptible mice to early- and late-onset autoimmune disease, and this is explicable by the relative paucity of the CD4+CD2.5+ regulatory T cells present early in life. We have now made a new and striking observation that further strengthens the paradigm. Autoantibody (autoAb) to the ovarian zona pellncida 3 (ZP3) B cell epitope (335-342) was found to preferentially injure ovaries in neonatal mice while sparing ovaries of adult mice. Interestingly, although the ovarian disease is triggered by ZP3 autoAb, disease expression depends on the presence of T cells in the neonate, and is associated with de nero neonatal autoimmane T cell response to ovarian antigen. In addition, induction of this neonatal AOD is B cell epitope-specific; thus autoAb to a second ZP3 native B cell epitope (171-180) is non-pathogenic. Even more exciting, neonatal AOD develops only when the autoAb first reaches the neonatal mice in the first 5 days of life. Theorem, maternal autoAb can trigger in neonates pathogenic autoi_une T ¿¿11_sponse and neonatal AOD; the di_ _duction i_ B cell epito_snecific, and only imvacts neonatal mi_ _t are known to be defi¿i_ in _gulato_ T cells. We now propose the following experimental approaches to further investigate these new and exciting observations. H_ we will test the hypothesis that neonatal AOD is triggered by epitope-specific autoAb, which forms immune complexes with endogenous Ag, to induce ZP3 specific pathogenic T celt response and tong-term autoimmune memory. Second, we will test the hypothesis that activation of antigen presenting cells by immune complex is dependent on their Fc receptor, and this event is required for neonatal AOD induction. Third, we will test the hypothesis that CD4+ CD25+ regulatory T cell deficiency in neonatal mice explains the propensity of neonatal mice to develop autoimmune response and disease. This proposal will therefore address fundamental mechanisms responsible for autoimmune induction and prevention, and specifically, neonatal autoimmane diseases including systemic lupus-related congenital heart block. PERFORCE Si_(S) (organizatiocnit,y,state) Universityof Virginia CiaariottesvilteV, irginia KEY PERSONNEL ========================================Section End===========================================